Therapeutic compositions and method

ABSTRACT

A COMPOSITION HAVING BRADYCARDIA AND ISOPROTERENOL ACTIVITY COMPRISING AT LEAST ONE COMPOUND SELECTED FROM THE GROUP CONSISTING OF RACEMATES OF 1-PHENOXY-2-HYDROXY-3-TERT.-BUTYLAMINO PROPANES OF THE FORMULA   (R1,R2,R-PHENYL)-O-CH2-CH(-OH)-CH2-NH-C(-CH3)3   WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF ALKYNYLOXY OF 2 TO 4 CARBON ATOMS, -(CH2)X+1-OH, -(CH2)X-CN AND -(CH2)X-NH2, WHERE X IS AN INTEGER FROM 0 TO 3, COOH AND COOR&#39;&#39; WHERE R&#39;&#39; IS ALKYL OF 1 TO 4 CARBON ATOMS, R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKOXY AND ALKYLTHIO OF 1 TO 4 CARBON ATOMS, -CN AND ALKENYL AND ALKYNYL OF 2 TO 4 CARBON ATOMS AND R2 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALOGEN AND ALKYL AND ALKOXY OF 1 TO 4 CARBON ATOMS, THEIR OPTICALLY ACTIVE ISOMERS AND THEIR NONTOXIC, PHARRMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OF SAID RACEMATES AND SAID OPTICALLY ACTIVE ISOMERS AND A MAJOR AMOUNT OF A PHARMACEUTICAL CARRIER AND METHOD OF PRODUCING BRADYCARDIA AND SUPPRESSING TACHYCARDIA EFFECTS OF N-ISOPROPYL-NORADRENALINE IN WARM-BLOODED ANIMALS.

United States Fatent O 3,740,444 THERAPEUTIC COMPOSITIONS AND METHOD Herbert Koppc, Ingelheim tlihine), Albrecht Engelhardt,

Mainz (Rhine), and Karl Zeile, Ingelheim (Rhine), Germany, assignors to Boehringer llngelheim G.m.b.I-I., Ingelheirn (Rhine), Germany No Drawing. Continuation-impart of application Ser. No. 700,376, Jan. 25, 1968, now Pat. No. 3,541,130. This application May 12, 1970, Ser. No. 36,676

Int. Cl. A61k 27/00 US. Cl. 424330 11 Claims ABSTRACT OF THE DISCLOSURE A composition having bradycardia and isoproterenol activity comprising at least one compound selected from the group consisting of racemates of l-phenoxy-Z-hydroXy-3-tert.-butylamino propanes of the formula wherein R is selected from the group consisting of alkynyloxy of 2 to 4 carbon atoms, -(CH OH, (CH CN and (CH NH Where x is an integer from to 3, COOH and COOR' Where R is alkyl of 1 to 4 carbon atoms; R is selected from the group consisting of hydrogen, alkoxy and alkylthio of 1 to 4 carbon atoms, CN and alkenyl and alkynyl of 2 to 4 carbon atoms and R is selected from the group consisting of hydrogen, halogen and alkyl and alkoxy of 1 to 4 carbon atoms, their optically active isomers and their nontoxic, pharmaceutically acceptable acid addition salts of said racemates and said optically active isomers and a major mount of a pharmaceutical carrier and method of producing bradycardia and suppressing tachycardia effects of N-isopropyl-noradrenaline in Warm-blooded animals.

PRIOR APPLICATION This application is a continuation-in-part application of our copending commonly-assigned US. patent application Ser. No. 700,376 filed Jan. 25, 1968, now US. Pat. No. 3,541,130.

OBJECTS OF THE INVENTION It is an object of the invention to provide novel compositions having bradycardia and isoproterenol activity.

It is another object of the invention to provide novel method of inducing bradycardia and isoproterenol-antago nistic activity in warm-blooded animals.

These and other objects and advantages of the invention will become obvious from the following detailed description.

THE INVENTION The novel compositions of the invention having bradycardia and isoproterenol antagonistic activity are comprised of at least one compound selected from the group consisting of racemates of 1-phenoXy-2-hydroXy-3-tert.- butylamino propanes of the formula wherein R is selected from the group consisting of alkynyloxy of 2 to 4 carbon atoms, -(CH OH, -(CH -CN and (CH NH Where x is an integer from 0 to 3, COOH and COOR' where R is alkyl of 1 to 4 carbon atoms; R, is selected from the group consisting of hydrogen, alkoxy and alkylthio of 1 to 4 carbon atoms, CN and alkenyl and alkynyl of 2 to 4 carbon atoms and R is selected from the group consisting of hydrogen, halogen and alkyl and alkoxy of l to 4 carbon atoms, their optically active isomers and their non-toxic, pharmaceutically acceptable acid addition salts of said racemates and said optically active isomers and a major amount of a pharmaceutical carrier.

Examples of non-toxic, pharmacologically acceptable acids suitable for addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and organic acids such as methane sulfonic acid, acetic acid, lactic acid, tartaric acid, ascorbic acid, S-chlorotheophylline and the like.

The compounds according to the present invention may be prepared by a number of different methods involving known chemical reaction principles; however, among these, the following methods have been found to be most convenient and efficient:

METHOD A By reacting an epoxide of the formula R2 (II) where the Rs have the same meanings as in Formula I, with tert.-butylamine in the presence of an inert organic solvent, such as ethanol.

METHOD B By reacting a l-substituted phenoXy-2-hydroxy-3-halo propane of the formula wherein the Rs have the same meanings as in Formula I and Hal is halogen, with tert.-butylamine in the presence of an inert organic solvent, such as ethanol.

The starting compounds of the Formulas II to III for the above methods are known compounds or may readily be prepared by known methods. For example, the substituted l-phenoxy-2,3-epoxy propanes of Formula 11 may be prepared by reacting a corresponding substituted phenolate of Formula VI under alkaline conditions with a 1-halo-2,3-epoxy propane such as epichlorohydrin. Most of the corresponding phenols are known in the prior art and they are easily obtainable by conventional methods. Cyanophenols, particularly those with alkyl and/or alkoxy groups, may be prepared by splitting olf water from the correspondingly substituted phenolic benzaldoximes which are prepared from known phenolic benzaldehydes. Cyanophenols with-an allyl substituent are obtained by reacting the cyanophenol with allyl bromide with rearrangement of the intermediate allyl ether into the final product. Halocyanophenols are obtained by reacting the cyanophenol with a hydrogen halide in the presence of H 0 Cyanomethylphenols can be made by introducing a nitro group into a benzylnitrile and converting it into a phenol group by reducing, diazotizing and boiling down. The aminoalkyl substituted compounds of Formula I are prepared by reduction of the corresponding cyano or cyanoalkyl substituted compounds, which in turn can be obtained by method A.

The amino-substituted compounds of Formula I are prepared by reacting the corresponding nitrophenols with epichlorohydrin to form the corresponding 2,3-epoxy' compound which is reacted with tert.-butylamine and then the nitro group is reduced to the amino group. The hydroxyalkylphenols may be prepared by reduction of the appropriate phenolic benzaldehyde which is then reacted with epichlorohydrin and then with tert.-butylamine. The propargyl oxyphenols can be prepared by reacting propargyl bromide with the appropriate diphenol such as pyrocatechol by heating without any disubstitution which requires more severe reaction conditions. Other processes are described in Belgian Pat. No. 641,133 and in the literature.

The free bases of Formula I obtained by any of the above methods, A through G, may subsequently be transformed into non-toxic, pharmacologically acceptable acid addition salts by conventional methods, that is, by acidifying a solution of the free base with the desired acid and recovering the acid addition salt by evaporation of the solvent or by precipitation, for instance.

The compounds of the general Formula I possess on the --CHOH- grouping an asymmetric C-atorn, and consequently, occur in the form of racemates as well as in the form of optically active antipodes. Th'e optically active compounds can be obtained in that one proceeds either from optically active starting compounds or that the racemates obtained are split into their optical antipodes in the usual manner, for example, by means of dibenzoyl-D-tartaric acid or D-3-bromocamphor-8-sulfonic acid or d-i-p-toluyl-d-tartaric acid.

The said compositions of the invention produce bradycardia and at the same time act as N-isopropylnoradrenaline (isoproterenol) antagonists as shown in dogs and guinea pigs. Thus, the tachycardiac eifects caused by the administration of N-isopropyl-noradrenaline are suppressed or eliminated by prior administration of one of the compositions of the present invention, and cardiac arrhythmia are equalitzed by them. In other words, the compositions of the invention block the sympathetic nervous system of the heart. Consequently, the areas of indication for the compositions, of the present invention are hypertension, angina pectoris, cardiac arrhythmia, digitalis intoxication and pheochromocytoma disorders. They may also be used in conjunction with coronary dilator or sympathicomimetic agents. The compositions may be in the form of injectable solutions or suspensions, tablets, drages, sustained release tablets, etc. the usual useful dose is 1 to 300 mg, preferably 1 to 150 mg., for oral administration and 11 to 20 mg. for parenteral administration.

The novel method of the invention of inducing bradycardia and of suppressing tachycardiac eifects of N-isopropyl-noradrenaline in warm-blooded animals comprises administering to warm-blooded animals a safe and effective amount of at least one of the compounds of Formula I. The said compounds may be administered orally parenterally or rectally. The usual dosage is 0.002 to mg./kg., depending upon the method of administration.

In the following examples there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE I Preparation of 1-(2-cyano-3-methyl-phenoxy)-2- hydroxy-3-tert.-butylamino propane.I-IC1 1-(2-cyano-3-methylphenoxy)-2,3-epoxy propane, prepared from 17 gm. (0.128 mol) of 2-cyano-3-methylphe- 1101 and 12.2 gm. (0.132 mol) of epichlorohydrin in 125 ml. of 1 N NaOH, was dissolved as a dark, impure viscous oil in 200 ml. of methanol, and 29 ml. of tertbutylamine were added thereto. After refluxing the mixture for 2 hours, the solvent was distilled off under vacuum, and the brown residue was extracted with dilute HCl. The clear solution was filtered over charcoal and was made alkaline with NaOH. The precipitating base was taken up in ether and the organic phase was separated and was washed repeatedly with water and dried over MgSO After concentration up to weight constancy, 4.5 gm. of a base remained and this was dissolved in a small amount of ethanol. The hydrochloride salt was precipitated by an addition of etheral HCl and was isolated as a solid product. It was recrystalized from acetonitrile with an addition of ether followed by a second recrystallization from ethanol with an addition of ether to obtain 1-(2-cyano 3 methylphenoxy)-2-hydroxy-3-tert.-butylamino propane hydrochloride having a melting point of 178-180" C. Using this same procedure, there was obtained 1-(2-cyanomethyl-3-methylphenoxy)-2-hydroxy-3- tert.-butylaminopropane hydrochloride.

EXAMPLE II Preparation of 1- 2-cyano-4-chlorophenoxy) -2-hydroxy- 3-tert.-butylamino propane.HCl

5.7 gm. (0.02 mol) of 1-(Z-cyanophenoxy)-2-hydroxy- 3tert.-butylamino propane (prepared analogously to Example -I) were dissolved in 32 ml. of concentrated HCl and while stirring at 45 C., 2.27 gm. of 35% hydrogen peroxide were added dropwise so that the temperature did not exceed 65 C. Thereafter, the temperature was maintained at 60 C. for 30 minutes and the mixture was concentrated in vacuo at the end of which a sglid residue remained. The raw hydrochloride was recrystallized from ethanol under an addition of ether to obtain 3 gm. of 1- (2-cyano-4-chlorophenoxy)-2-hydroxy 3 tert.-butylamino propane hydrochloride having a melting point of 180-182" C.

EXAMPLE III Preparation of 1-(2-methyl-4-cyanophenoxy)-2-hydroxy- 3-tert.-butylamino propanel-ICI 24 gm. of 1-(2-methyl-4-cyanophenoxy)-2,3-epoxypropane in 150 ml. of ethanol were reacted with 25 ml. or" tert.-butylamine. After refluxing the reaction mixture for 2 hours, the solvent was distilled off in vacuo, and the residue was dissolved in dilute HCl. After extraction with ether, the aqueous phase was made alkaline with NaOH and the precipitated base was taken up in ether. The ether solution was washed with H O, dried over MgSO and finally the ether was distilled off. The residue was dissolved in ml. of ethanol and ethereal l-ICl was added thereto. The precipitating crystalline hydrochloride was isolated and recrystallized from methanol with an addition of ether to obtain 17 gm. of pure 1-(2- methyl-4-cyanophenoxy)2-hydroxy 3 tert.-butylamino ggopage hydrochloride having a melting point of 230- EXAMPLE IV Preparation of 1-(2-methoxy-4-cyanophenoxy) -2-hydroxy-3-tert.-butylamino propane.HCl

9.9 gm. (0.048 mol) of 1-(2-methoxy-4-cyanophenoxy)-2,3-epoxy propane in 100 ml. of ethanol were heated with 14.6 gm. (0.02 mol; 21 mol.) of tert.butylamine for 3 hours over a water bath. After distillation of the solution in vacuo, the residue was digested with dilute HCl and the solution was separated from the insoluble matter. The aqueous phase was made alkaline with NaOH and the precipitated base was extracted with ether, washed with water, and the organic phase was dried over MgSO After distilling off the ether, the oily residue was dissolved in ethanol, admixed with ethereal HCl, and the precipitating crystals of 1-(2-methoxy-4-cyanophenoxy)-2-hydroxy- 3-tert.-butylamino propane hydrochloride were vacuum filtered and recrystallized from ethanol with an addition of ether to obtain 7.1 gm. of the product having a melting point of 2l0213 C.

EXAMPLE v 6.3 gm. (0.02 mol) of 1-(2-cyano-4chlorophenoxy)-2- hydroxy-3-tert.-butylamino propane hydrochloride were dissolved in 100 ml. of methanol containing ml. of NH;. and the mixture was hydrogenated under normal pressure at C. over Raney-nickel. After separation of the catalyst, the solvent was distilled off in vacuo, and the residue was admixed with ether and water. After an addition of a small amount of NaOH, the aqueous phase was separated and the organic phase was Washed with water and dried over MgSO After distilling off the ether, a solid residue remained which was recrystallized from ethyl acetate with an addition of petroleum ether to obtain I-(Z-aminomethyl 4 chlorophenoxy)-2hydroxy-3- tert.-butylamino propane. The base was dissolved in ethanol and ethereal HCl was added thereto. The precipitated crystals of the hydrochloride of the base were isolated to obtain 3.1 gm. of the hydrochloride having a melting point of 118-120 C.

EXAMPLE VI Using the procedure of Example V, 1-(2-methoxy-4- Using the procedure of Example V, 1-(2-cyanophenoxy)-2-hydroxy-S-terL-butylamino propane hydrochloride was hydrogenated to obtain 1-(2-aminomethylphenoxy)- 2-hydroxy-3-tert.-butylamino propane dihydrochloride having a melting point of 220-222 C.

EXAMPLE. VIII Using the procedure of Example 1V, 1-(2-methoxycarbonylphenoxy)-2,3-epoxy-propane was reacted with tert.-butylamine to form 1-(2-methoxycarbonylphenoxy)- 2-hydroxy-3-tert.-butylamino propane hydrochloride having a melting point of 144-146 C.

EXAMPLE IX By saponification of 1-(2-methoxycarbonylphenoxy)-2- hydroxy-3-tert.-butylamino propane with sodium hydroxide, there was obtained 1-(2-hydroxycarbonylphenoxy)-2-hydroxy-3tert.-butylamino propane hydrochloride having a melting point of 138140 C.

EXAMPLE X Using the procedure of Example IV, tert.-butylamine and 1-(2-methoxy-5-cyanophenoxy)2,3-epoxy propane were reacted to obtain 1-(2-methoxy-5-cyanophenoxy)-2- hydroxy-3-tert.-butylamino propane hydrochloride having a melting point of 149152 C.

EXAMPLE XI Using the procedure of Example 1V, tert.-butylamine and 1-(4-methoxycarbonylphenoxy)-2,3,-epoxy propane were reacted to form 1-(4-methoxycarbonylphenoxy)-2- hydroxy-3-tert.-butylamino propane hydrochloride having a melting point of 205-207 C.

EXAMPLE XII Using the procedure of Example 1V, tert.-butylamine and 1 (2-hydroxymethylph'enoxy)-2,3-epoxy propane were reacted to form 1-(Z-hydroxymethylphenoxy)-2-hydroxy-3-te1t-butylamino propane oxalate having a melting point of 180-183" C.

EXAMPLE XIII 1-(4-methoxycarbonylphenoxy) 2 hydroxy 3-tert. butylamino propane was chlorinated analogous to Example II to obtain 1-(2-chloro-4-methoxycarb0nylphenoxy)- 2-hydr0xy-3-tert.-butylamino propane hydrochloride having a melting point of 208-210 C.

EXAMPLE XIV Using the procedure of Example IV, 20 gm. of 1-(3- hydroxymethylphenoxy)-2,3-epoxy propane and 18.5 gm. of tert.-butylamine were reacted to obtain 1-(3-hydroxymethylphenoxy) 2 hydroxy-3-tert.-butylamino propane having a melting point of 82-84 C.

EXAMPLE XV Preparation of 1-(2-cyanophenoxy)-2-hydroxy-3-tert.- butylamino propane.HCl

15 gm. (0.085 mol) of 1-(2-cyanophenoxy)-2,3-epoxy propane were dissolved in ml. of ethanol and 18.6 gm. (0.255 mol) of tert.-butylamine were added thereto. After standing for 1 hour at room temperature, the solution was heated at 60-70" C. for 2 hours after which the volatile constituents were distilled otf in vacuo. The residue was digested with dilute HCl, and the insoluble constituents were vacuum filtered olf. Then the filtrate was made alkaline with NaOH and the precipitating base was taken up in ether. After the ether solution had been dried over MgSO the ether was distilled 01f and the residue was dissolved in ethanol and by addition of etheral HCl, the hydrochloride was precipitated therefrom in crystal line form which after recrystallization from ethanol with an addition of ether gave 9.8 gm. of 1-(2-cyanophenoxy)- 2-hydroxy-3-tert.-butylamino propane hydrochloride having a melting point of 163-165 C EXAMPLE XVI Preparation of 1-(4-cyanophenoxy)-2-hydroxy-3-tert.- butylaminO-propane.HCl

5.7 gm. (0.02 mol) of 3-tert.-butyl-5-(4-cpanophenoxymethyl)-oxazolidinone-(2) were dissolved in 50 ml. of ethanol. After addition of a solution of 10 gm. of potassium hydroxide in 15 ml. of water, the solution was refluxed for 2 hours and then the ethanol was distilled off in vacuo, and the residue was extracted with ether. The ethereal phase was separated, dried over MgSO and the MgSO was filtered olf. After concentration of the ether solution, the solid raw base was recrystallized from ethyl acetate to obtain a product having a melting point of l00105 C. After dissolving the crystalline base in ethanol, ethereal hydrochloric acid was added and the solid was isolated and again recrystallized from ethanol/ ether to obtain 1.9 gm. of 1-(4-cyanophenoxy)-2-hydroxy- 3-tert.-butylamino propane hydrochloride having a melting point of l87189 C.

EXAMPLE XVII Preparation of 1-(3-cyanophenoxy)-2-hydroxy-3-tert.- butylamino-Z-propane oxalate 9.6 gm. (0.05 mol) of 1-(3-cyanophenoxy)-2-hydroxy- 3-arnino propane were dissolved in 40 ml. of dimethylformamide and 100 ml. of tetrahydrofuran and 4.2 gm. (0.05 mol) of pulverized sodium bicarbonate were added thereto. Then, 6.9 gm. (0.05 mol) of tert.-butylbromide were added and the mixture was refluxed for 24 hours. After the mixture had been cooled, the inorganic solid was filtered off and the solvent mixture was distilled off in vacuo. The residue was dissolved by heating in ethyl acetate and the insoluble inorganic portions were vacuum filtered ofr and the filtrate was admixed with petroleum ether. The base precipitated in solid form and was isolated and recrystallized from ethyl acetate with an addition of petroleum ether to obtain 1-(3-cyanophenoxy)-2-hydroxy-3-tert.-butylamino propane having a melting point of 108110 C.

After having been dissolved in ether, the said product was admixed with an etheral oxalic acid solution whereby the oxalate precipitated in amorphous form. It was isolated, dissolved in a small amount of ethanol and slowly ether Was added thereto. 2.7 gm. of the oxalate salt occurred in colorless crystalline form and after being vacuum filtered and dried, melted at 154157 C. under decomposition.

EXAMPLE XVIII Preparation of 1-(2-propargyloxyphenoxy)-Z-hydroxy- 3-tert.-butylamino propane oxalate 7.15 gm. (0.035 mol) of 1(2-propargyloxyphenoxy)- 2,3-epoxy propane were dissolved in 70 ml. of ethanol and after 11 gm. (0.15 mol) of tert.-butylamine were added thereto, the mixture Was refluxed for 2 hours. After the mixture was cooled, the solvent was distilled oif in vacuo and the oily residue was digested with dilute HCl. The aqueous phase was extracted with ether and the acid, aqueous solution was then made alkaline with NaOH. The base precipitating in oily form was taken up in ether and the organic phase was washed with Water and dried over MgSO After the ether had been distilled ofi, the residue was dissolved in absolute ether, and a solution of 2 gm. of oxalic acid in 10 ml. of acetone was added. The precipitating oxalate was recrystallized from ethanol with an addition of ether to obtain 4.6 gm. of -1-(2-propargyloxyphenoxy) 2 hydroxy 3-tert.-butylamino propane oxalate having a melting point of 132-134 C.

EXAMPLE XIX 1 (2 nitro-4-chlorophenoxy)-2-hydroxy-3-tert.-butylamino propane was hydrogenated in the presence of Raney-nickel in methanol to obtain l-(2-amino-4-chlorophenoxy)-2-hydroxy-3-tert.-butylamino propane dihydrochloride having a melting point of 260-262 C.

Using the same procedure of hydrogenation, there Were obtained 1-(2-amino-4-fluorophenoxy)-2-hydroxy-3-tert.- butylamino-propane dihydrochloride and 1 (2-nitro-4- bromophenoxy) -2-hydroxy-3-tert.-butylamino propane dihydrochloride.

EXAMPLE XX Preparation of 1-(2,4-dichloro-3-aminophenoxy)-2- hydroxy-3-tert.-buty1amino-propane.HCl

8.05 gm. of 1-(3-nitrophenoxy)-2-hyroxy-3-tert.-butylamino-propane were dissolved in 100 cc. of concentrated hydrochloric acid with stirring and the resulting solution was heated to 45 C. Then, 11.3 gm. (0.1 mol) of 30% hydrogen peroxide solution were added dropwise while holding the temperature between 50 and 60 with stirring. After 30 minutes, an oil separated and excess hydrochloric acid was distilled off in vacuo. The residue was taken up in water and the mixture was made alkaline with sodium hydroxide. The resulting free base precipitated as an oil and was dissolved in ethyl acetate. The said solution was washed With water, dried and evaporated to dryness to obtain 9.2 gm. (0.0273 mol) of 1-(2,4-dichloro- 3-nitrophenoxy)-2-hydroxy-3-tert.-butylamino-propane.

The 9.2 gm. of the said base were dissolved in 150 cc. of methanol and the said base Was hydrogenated in the presence of a Raney-nickel catalyst at room temperature and normal pressure until the theoretical amount of hydrogen (1240 cc.) Was adsorbed (2% hours). The catalyst was then removed by suction filtration and the sol.- vent was distilled off in vacuo. The residue was dissolved in ethanol and the resulting solution was acidified with etherified hydrochloric acid and extracted with ether. After standing in the cold, the dihydrochloride of 1-(2,4-dichloro 3 aminophenoxy)-2-hydroxy-3-tert.4butylaminopropane crystallized out. After recrystallization twice from acetonitrile, there was obtained 2.5 gm. of the dihydrochloride melting at 166169 C.

8 Pl-MRMACEUTICAL EXAMPLES Example A--Tablets Parts 1 (2 hydroxyrnethylphenoxy)-2-hydroxy-3-tert.

butylamino propane.HCl 35.0

2,6-bis-(diethanolamino)-4,8-dipiperidino-pyrimidopyrimidine 75.0 Lactose 164.0 Corn starch 194.0 Colloidal silicic acid 14.0 Polyvinylpyrrolidone 6.0 Magnesium stearate 2.0 Soluble starch 10.0

1 (2 cyano-3-n1ethyl-phenoxy)-2-hydroxy-3-tert.-

butylamino propane hydrochloride 40.0 Corn starch 164.0 Potassium phosphate 240.0 Magnesium stearate 1.0

1 (2 cyano-3-methylphenoxy)-2-hydroxy-3-tert.

butylamino propane hydrochloride 50.0

2,6-bis-(diethanolamino)-4,8-dipiperidinopyrimido- [5,4-d]-pyrimidine 75.0 Lactose 164.0 Corn starch 194.0 Colloidal silicic acid 14.0 Polyvinylpyrrolidone 6.0 Magnesium stearate 2.0 Soluble starch 10.0

The individual components are intensively admixed and the mixture is granulated in the usual manner. The granulate is compressed into 1000 tablets of 500 mg., 445 mg. or 515 mg.

Example B-Gelatin capsules The content ofthe capsules is composed as follows:

Mg. 1 (3 hydroxymethylphenoxy)-2-hydroxy-3-tert.-

butylamino propane.HCl 25.0 Corn starch 175.0

Mg. 1 (2 cyano-4-chlorophenoxy)-2-hydroxy-3-tert.-

butylamino propane maleinate 25.0 Corn starch 175.0

The ingredients are intensively admixed and 200 mg. portions of the mixtures are filled into gelatin capsules of suitable size. Each capsule contains 25 mg. of the optically active substance.

Example CInjectable solution Parts 1 (2 methyl-4-cyanophenoxy)-2-hydroxy-3-tert.-

butylamino propane hydrochloride 2.5 Sodium salt of EDTA (ethylenediaminetetraacetic acid) 0.2

Distilled water, ad. 100.0 parts.

Preparation The active substance and the EDTA-salt were dissolved in sufiicient water and distilled water to the desired volume was added. The solution was filtered free of suspended particles and filled into 1 cm.-ampules under aseptic conditions. Then, the ampules were sterilized and sealed so that each of these ampules contained 25 mg. of active substance.

Example DSustained release tablets The active substance, the carboxymethylcellulose and the stearic acid are intensively admixed and the mixture is granulated in the usual manner, a solution of the cellulose acetate phthalate in 200 ml. of a mixture of ethanol and ethylacetate is used for this purpose. The granulate is then compressed into 380 mg. kernels, which are in the usual manner coated with a sugar containing solution of polyvinylpyrrolidone in water. Each tablet contains 25 mg. of active ingredients.

PHARMACOLOGICAL DATA The compounds of the invention were tested for fl-adrenergic blocking activity in adult laboratory guinea pigs under urethane anaesthesia.

The bradycardia activity of the compounds was determined by administering the test compounds by intravenous injection at 5 progressively increasing dosages (0.1 mg./ kg., 0.3 mg./kg., 1 mg./kg., 3 ing/kg. and mg./kg. for each compound) to 4 animals per compound and ascertaining the decrease of the basic frequency of the heart beat by means of an electrical recorder.

After each determination of the decrease of the basic frequency, 1 'y/kg. of isoproterenol [=04 (isopropylaminomethyl) protocatechuyl alcohol] was administered to the same animal by intravenous injection, and the maximum frequency change was determined.

The results of both determinations (bradycardia activity and isoproterenol antagonistic activity) were plotted as a doseactivity curve, and the curve for each compound was compared with a corresponding curve for the standard control compound dichlorisoproterenol (DCI), a known effective S-adrenergic blocking agent. The following results were obtained.

TABLE I Isoproterenol Bradycardia antagonistic activity, activity, Compound x D OI x D CI 1-(2-hydroxymethylphenoxy)-2-hydroxy- 3-tert-.butylamino propane-H01 8 24 1-(3-hydroxymethylphenoxy)-2-hydroxy- 3-tert.-butylamino propane- H01 8 20 1-(2-1nethoxy-5-cyanophenoxy)-2-hydroxy- 3-tert.-butylamino-propane- HCl 6. 5 10. 9 1-(2-cyano-3-methylphenoxy)-2-hydr0xy- 3-tert-.butylamino propane-H01 10 60 1-(amethylt-cyanopheuoxy) '21'1YdlOXY' 3-tert.-butylamino propane-H01 43 33 1-(Z-propargyloxyphenoxy)-2-hydroxy-3- tert--butylamino propane-oxalate. 12. 2 32. 6 1-(2,4-dichloro-3-aminophenoxy)-2-hydroxy- 3-tert--butylamino propane-21101. 59 63 Various modifications of the compositions and method of the invention may 'be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only as defined in the appended claims.

We claim:

1. A composition having bradycardia and isoproterenol antagonistic activity comprising a small but effective amount of an active compound selected from the group consisting of a racemate of a 1-phenoxy-2-hydroxy-3-tert.- butylamino propane of the formula wherein R is selected from the group consisting of alkynyloxy of 2 to 4 carbon atoms and (CH --OH, where x is an integer from 0 to 3; R is selected from the group consisting of hydrogen, alkoxy and alkylthio of 1 to 4 carbon atoms and alkenyl and alkynyl of 2. to 4 carbon atoms and R is selected from the group consisting of hydrogen, halogen and alkyl and alkoxy of 1 to 4 carbon atoms, an optically active isomer thereof a non-toxic, pharmaceutically acceptable acid addition salt of said racemate and said optically active isomer and a major amount of a pharmaceutical carrier.

2. A composition of claim 1 wherein the amount of active ingredient is 1 to 300 mg.

3. A composition of claim 1 wherein R is hydrogen.

4. A composition of claim 1 wherein the active compound is 1-(2-hydroxy-methylphenoxy)-2-hydroxy-3-tert.- butylamino propane and a non-toxic, pharmaceutically acceptable acid addition salt thereof.

5. A composition of claim 1 wherein the active compound is 1-(3-hydroxy-methylphenoxy)-2-hydroxy-3-tert.- butylarnino propane and a non-toxic, pharmaceutically acceptable acid addition salt thereof.

6. The composition of claim 1 wherein the active compound is 1-(2-proparglyoxyphenoxy)-2-hydroxy-3-tert.- butylamino propane or a non-toxic, pharmaceutically acceptable acid addition salt thereof.

7. A method of producing bradycardia and suppressing tachycardiac effects of N-isopropyl-noradrenaline in warm-blooded animals which comprises administering to Warm-blooded animals a safe and effective amount of a compound selected from the group consisting of a racemate of a 1-phenoxy-3-hydroxy-3-tert.-butylamino propane of the formula wherein R is selected from the group consisting of alkynyloxy of 2 to 4 carbon atoms and (CH -OH, where x is an integer from 0 to 3; R is selected from the group consisting of hydrogen, alkoxy and alkylthio of 1 to 4 carbon atoms and alkenyl and alkynyl of 2 to 4 carbon atoms and R is selected from the group conssisting of hydrogen, halogen and alkyl and alkoXy of 1 to 4 carbon atoms, an optically active isomer thereof and a non-toxic, pharmaceutically acceptable acid addition salt of said racemate and said optically active isomer.

8. The method of claim 7 wherein the active compound is 1-( 2 hydroxymethylphenoxy)-2-hydroxy-3-tert.-butylamino propane or a non-toxic, pharmaceutically acceptable acid addition salt thereof.

9. The method of claim 7 wherein the active compound is 1-(3 hydroxymethylphenoxy)-2-hydroXy-3-tert.-butyl amino propane or a non-toxic, pharmaceutically acceptable acid addition salt thereof.

10. The method of claim 7 wherein the active com- 1 pound of 1 (2 hydroxymethoxyphenoxy)-2-hydroxy-3- a tert.-butylamino propane or a non-toxic, pharmaceutically" acceptable acid addition salt thereof.

11. The method of claim 7 wherein the active com-- 12 pound is 1-(2 propargyloxyphenoxy)-2-hydroxy-3-tert.- butylamino propane or a non-toxic, pharmaceutically acceptable acid addition salt thereof.

References Cited UNITED STATES PATENTS STANLEY J. FRIEDMAN, Primary Examiner U.S. Cl. X.R. 42 4-304, 308, 317

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 3,7QOJHM June 19,1973

Decent No Dated Inventofls) HERBERT KOPPE, ALBRECHT ENGELHARDI and KARL ZEILE it; is certified that error appears in the above-identified patent that said Letters Patent are hereby corrected as shown below:

5 Col. 1 Recite. priority of 3 German Applications,

Line 9 B 91 070 filed Feb. 6, 1967 B 93 025 Jun. 15; 1967' B 93 6 5 u y s, 19 7 British Application 2764 /67, filed June 15, 1967 and supplemental examp1es.--

Signed end sealed this 18th day of December 1973 (SEAL) Attest;

EDWARD M, FLETCHER, JR. 1 RENE D. TEGTMEYER Attesting; Officer Acting Commissioner of Patents 

